Heterobicyclic derivatives

Abstract

Heterobicyclic derivatives of the formula:whereinR<1 >is aryl which may have suitable substituent(s), ar(lower)alkyl which may have suitable substituent(s), halo(lower)alkyl, protected carboxy(lower)alkyl, acyl(lower)alkyl, heterocyclic group or heterocyclic(lower)alkyl which may have suitable substituent(s),R<2 >is aryl which may have suitable substituent(s) or heterocyclic group, andR<3 >is hydrogen, lower alkoxy or arylthio,and a pharmaceutically acceptable salt thereof which are useful as a medicament.

What is claimed is:  
     
       1. A method for treating a disease or disorder mediated by phosphodiesterase IV (PDE-IV), tumor necrosis factor (TNF), or both, comprising administering an effective amount of a compound of formula (I) to a subject in need thereof, wherein the compound of formula (I) is:                    
       wherein R 1  is  
       aryl which may have one or more suitable substituent(s),  
       ar(lower)alkyl which may have one or more suitable substituent(s),  
       halo(lower)alkyl,  
       carboxyethyl,  
       protected carboxy(lower)alkyl,  
       acyl(lower)alkyl,  
       a heterocyclic group which may have one or more suitable substituent(s) or  
       a heterocyclic(lower)alkyl group which may have one or more suitable substituent(s);  
       R 2  is aryl which may have one or more suitable substituent(s) or a heterocyclic group, and  
       R 3  is hydrogen, lower alkoxy or arylthio,  
       or a pharmaceutically acceptable salt thereof;  
       provided that when R 1  is phenyl, halophenyl, trihalo(lower)alkyl, carboxyethyl, piperidyl, morpholinyl, piperazinyl, or alkylpiperazinyl, then R 2  is not substituted phenyl, piperidyl, morpholinyl, piperazinyl, or alkylpiperazinyl, and wherein the disease or disorder is selected from the group consisting of, osteoporosis, transplantation rejection, asthma, eosinophilia, cystic fibrosis, hepatitis, pancreatitis, nephritis, endotoxic shock, ankylosing spondylitis, an autoimmune hematological disorder, polychondritis, scleroderma, Wegener granulamotosis, dermatomyositis, chronic active hepatitis, atopic dermatitis, psoriasis, idiopathic sprue, autoimmune inflammatory bowel disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter's syndrome, non infection uveitis, autoimmune keratitis, interstitial lung fibrosis, psoriatic arthritis, cancer cachexia, AIDS cachexia, and thrombosis.  
     
     
       2. A method for treating hepatitis comprising: 
       administering an effective amount of the compound of formula (I) to a subject in need thereof,  
       wherein the compound of formula (I) is:                    
       wherein R 1  is  
       aryl which may have one or more suitable substituent(s),  
       ar(lower)alkyl which may have one or more suitable substituent(s),  
       halo(lower)alkyl,  
       carboxyethyl,  
       protected carboxy(lower)alkyl,  
       acyl(lower)alkyl,  
       a heterocyclic group which may have one or more suitable substituent(s) or  
       a heterocyclic(lower)alkyl group which may have one or more suitable substituent(s);  
       R 2  is aryl which may have one or more suitable substituent(s) or a heterocyclic group, and  
       R 3  is hydrogen, lower alkoxy or arylthio,  
       or a pharmaceutically acceptable salt thereof;  
       provided that when R 1  is phenyl, halophenyl, trihalo(lower)alkyl, carboxyethyl, piperidyl, morpholinyl, piperazinyl, or alkylpiperazinyl, then R 2  is not substituted phenyl, piperidyl, morpholinyl, piperazinyl, or alkylpiperazinyl.  
     
     
       3. The method of  claim 2  comprising treating a human subject.